Adoptive MHC-E-Restricted T Cell Therapy for the Treatment of Chronic Hepatitis B Virus Infection

过继性 MHC-E 限制性 T 细胞疗法治疗慢性乙型肝炎病毒感染

• 批准号: 10407461
• 负责人: Benjamin J Burwitz
• 金额: $ 57.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407461
• 关键词: Acute; Adoptive Transfer; Adult; Affect; Alleles; Animals; Avidity; Biological Assay; CD8-Positive T-Lymphocytes; Cell Line; Cells; Chronic Hepatitis B; Clinic; Coculture Techniques; Cytomegalovirus; Development; Dose; Epitopes; Exhibits; Frequencies; Goals; HIV; Hepatitis B Antigens; Hepatitis B Infection; Hepatitis B Virus; Hepatocyte; Human; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Lead; Liver; MHC Class II Genes; Macaca mulatta; Measures; Methods; Morbidity - disease rate; Mus; Nature; Pathogenicity; Patients; Peptides; Persons; Physiologic pulse; Polymerase; Population; Proteins; Research; Retroviridae; Rhesus; SIV; Sampling; Specificity; Surface; T cell receptor repertoire sequencing; T cell response; T cell therapy; T memory cell; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Traction; Translating; Transplant Recipients; Vaccinated; Vaccines; Virus Diseases; anti-viral efficacy; base; cytokine; design; exhaustion; extracellular; global health; humanized mouse; mortality; mouse model; novel; novel therapeutics; post-transplant; response; unvaccinated; vector

PROJECT SUMMARY Chronic hepatitis B virus infections (CHB) are recognized as a major global health concern. CHB affects 247 million people worldwide, and 887,000 die annually from associated liver complications. This high morbidity and mortality is exacerbated by the fact that treatments for CHB are rarely curative. Thus, there remains an urgent need to develop new therapeutic treatments for CHB that will lead to clearance or lasting suppression of infection. Here, we propose a new way to target HBV through the use of MHC-E-restricted CD8+ T cells. There are only two MHC-E alleles within the human population and they are functionally equivalent. Therefore, HBV-specific CD8+ T cells restricted by MHC-E should be effective in all patients with CHB. We will characterize the T cell receptors (TCRs) of MHC-E-restricted CD8+ T cells in rhesus macaques inoculated with a rhesus CMV vector that engenders large numbers of these unique responses. We will then test the ability of these TCRs to recognize and suppress HBV infection. Given the urgent need for tractable CHB therapeutics, we believe the research proposed herein to be of the highest significance.

项目摘要 慢性B型肝炎病毒感染（CH B）被认为是一个主要的全球健康问题。CHB影响247 全世界有100万人，每年有887，000人死于相关的肝脏并发症。这种高发病率 并且由于CHB的治疗很少能治愈的事实，死亡率更高。因此， 迫切需要开发新的治疗CHB的治疗方法，这将导致清除或持久抑制 感染 在这里，我们提出了一种通过使用MHC-E限制性CD 8 + T细胞靶向HBV的新方法。只有 人类群体中的两个MHC-E等位基因，并且它们在功能上是等同的。因此，HBV特异性 MHC-E限制的CD 8 + T细胞在所有CHB患者中均有效。我们将描述T细胞 用恒河猴CMV载体接种的恒河猴中MHC-E限制性CD 8 + T细胞的TCR 产生了大量独特的反应。然后，我们将测试这些TCR的能力， 识别和抑制HBV感染。鉴于对易于控制的CHB治疗的迫切需要，我们认为， 在此提出的研究具有最高的意义。